This Program Project application is based on our more than 6 years of ongoing collaborations to uncover the genes which control the development of spontaneous organ-specific autoimmune disease in the rat. Thin application constitutes three projects which are highly interactive to share resources including BB rats and proposed congenic lines, positional cloning reagents and expertise to provide cost saving research of genetic mechanisms of organ-specific autoimmunity. The Program Project investigators accomplishments include: 1) the establishment of the genetic map of the rat; 2) the mapping of the first diabetes gene (iddm1) to the lymphopenia (lyp) gene locus on chromosome 4 done in a cross between the inbred diabetes-prone (DP) and diabetes- resistant (DR) BB rats; 3) the development of a transspecies strategy to link the lymphopenia region to clone the lyp gene by position; 4) the linkage of the second diabetes gene (iddm2) to the major histocompatibility (MHC) gene locus (RT1BU) on chromosome 20 in a cross between DP BB rats and Lewis rats; 5) the preliminary and yet unpublished mapping in a cross with Fischer rats of a third diabetes gene (iddm3) to chromosome 2; 6) the evidence that the MHC (RT1.Bu/u) has a dominant susceptibility for thyroiditis and 6) the demonstration that the majority of the peripheral T cells pool in lyp/lyp rats consists of recent thymic emigrants with autoreactive properties. The projects are: Project 1: The P.I. will analyze the lymphopenia, insulitis and thyroiditis phenotypes using the above indicated strategy of BB rat breeding and cross-intercross analyses to produce congenic lyp/lyp, lyp/+ and +1+ BB DR and Fischer rats; Project 2: The P.I. will positionally clone lyp, characterize the expression of the lyp gene in the mouse and, in collaboration with Project 1, in the rat, and develop a mouse in which the lyp gene has been disrupted to replicate the lymphopenia phenotype: Project 3: The P.I. will analyze the third gene, iddm3, which confers susceptibility to diabetes and develop congenic animals for iddm3 as well as iddm1, clone and characterize iddm3 and identify other iddm genes with the use of the total genome scan strategy.